Process for the synthesis of derivatives of 2, 3-dihydro-1, 4-dioxino- [2, 3-f] quinoline

ABSTRACT

Methods of preparing compounds of Formula I  
                 
 
     are provided.

[0001] This application claims priority from co-pending provisionalapplication serial No. 60/291,547, filed on May 17, 2001, the entiredisclosure of which is hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] This invention relates to a novel process of producingderivatives of 2,3-dihydro-1,4-dioxino [2,3-f]quinoline in a highlyconvergent and efficient manner, as well as intermediates thereof.Compounds of the present invention are SSRI/5-HT_(1A) antagonists usefulfor the treatment of diseases which are caused or affected by disordersof the serotonin-affected neurological systems such as depression,including childhood depression, obsessive compulsive disorders, panicdisorder, generalized anxiety disorder, social anxiety disorders, sexualdysfunction, eating disorders such as bulimia, obesity, addictivedisorders caused by ethanol or cocaine abuse and dysthymia as describedin copending application No. 60/275,564 filed Mar. 14, 2001.

SUMMARY OF THE INVENTION

[0003] In accordance with the present invention is provided methods ofmaking compounds of Formula I:

[0004] wherein

[0005] R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy oftwo to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms;

[0006] R², R³, R⁴, and R⁶ are, independently, hydrogen, hydroxy, halo,cyano, carboxamido, carboalkoxy of two to six carbon atoms,trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbonatoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylaminoin which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms

[0007] R⁵ is hydrogen or alkyl of 1 to 6 carbon atoms;

[0008] A dotted line represents an optional double bond;

[0009] A and D are selected from carbon, substituted by R¹, andnitrogen, provided that at least one of A and D is nitrogen;

[0010] E and G are carbon, substituted by R¹; and

[0011] Z is N or CR⁶;

[0012] or pharmaceutically acceptable salts thereof, comprising thesteps of:

[0013] a) halogenating a compound of the formula:

[0014] wherein R′ is alkyl of 1-6 carbon atoms;

[0015] with a halogenating reagent to afford a compound of the formula:

[0016] wherein X is Br, Cl, or I;

[0017] b) dealkylating the compound of Formula 3 in an acid to afford acompound of the formula:

[0018] c) alkylating the compound of Formula 4 with R″ protectedglycidyl ethers

[0019] wherein R″ is benzyl or substituted benzyl to afford compound ofthe formula:

[0020] d) cyclizing the compound of Formula 5 with palladium or coppercatalyst to afford a compound of the formula:

[0021] e) debenzylating the compound of Formula 6 to afford the compoundof the formula:

[0022] f) activating the hydroxy moiety of the compound of Formula 7with a sulfonating reagent to afford a compound of the formula:

[0023] wherein R′″ is an aryl-, or alkyl-sulfonate and

[0024] g) coupling the compound of Formula 8 with the appropriateazaheterocycle of Formula 9

[0025] in the presence of base to provide a compound of Formula I.

[0026] In alternative embodiments of the present invention the hydroxymoiety of compounds of Formula 7 may be activated to halide to afford acompound of the formula:

[0027] wherein X is I, Br, or Cl and

[0028] the compound of Formula 10 may be coupled with the appropriateazaheterocycle of Formula 9

[0029] in the presence of base to provide a compound of Formula I.

[0030] In other embodiments of the present invention are providedmethods of making compounds of Formula I

[0031] comprising the steps of:

[0032] a) halogenating a compound of the formula:

[0033] wherein R′ is alkyl of 1-6 carbon atoms;

[0034] with a halogenating reagent in a solvent to afford a compound ofthe formula:

[0035] wherein X is Br, Cl, or I;

[0036] b) dealkylating the compound of Formula 3 in an acid to afford acompound of the formula:

[0037] c) alkylating the compound of Formula 4 with R″ protectedglycidyl ethers

[0038] wherein R″ is benzyl or substituted benzyl to afford compound ofthe formula:

[0039] d) cyclizing the compound of Formula 5 with palladium or coppercatalyst to afford a compound of the formula:

[0040] e) debenzylating the compound of Formula 6 to afford the compoundof the formula:

[0041] f) activating the hydroxy moiety of the compound of Formula 7with a sulfonating reagent to afford a compound of the formula:

[0042] wherein R′″ is an aryl- or alkyl-sulfonate; and

[0043] g) coupling the compound of Formula 8 with the appropriateazaheterocycle of Formula 9

[0044] in the presence of base to provide a compound of Formula I.

[0045] In alternative embodiments of the present invention the hydroxymoiety of compounds of Formula 7 may be activated to halide to afford acompound of the formula:

[0046] wherein X is I, Br, or Cl and

[0047] the compound of Formula 10 may be coupled with the appropriateazaheterocycle of Formula 9

[0048] in the presence of base to provide a compound of Formula I.

[0049] In some embodiments of the-present invention is provided a methodof making a compound of Formula Ia

[0050] comprising the steps:

[0051] a) halogenating a compound of the formula:

[0052] wherein R′ is alkyl of 1-6 carbon atoms;

[0053] with a halogenating reagent to afford a compound of the formula:

[0054] wherein X is Br, Cl, or I;

[0055] b) dealkylating the compound of Formula 3a in an acid to afford acompound of the formula:

[0056] c) alkylating the compound of Formula 4a with R″ protectedglycidyl ethers

[0057] wherein R″ is benzyl or substituted benzyl; to afford a compoundof the formula:

[0058] d) cyclizing the compound of Formula 5a with palladium or coppercatalyst to afford a compound of the formula:

[0059] e) debenzylating the compound of Formula 6a to afford a compoundof the formula:

[0060] f) activating the hydroxy moiety of the compound of Formula 7awith a sulfonating reagent to afford a compound of the formula:

[0061] wherein R′″ is an aryl- or alkyl-sulfonate; and

[0062] g) coupling the compound of Formula 8a with3-tetrahydropyridinyl-indole in the presence of base to provide acompound of Formula Ia.

[0063] Alternatively, the hydroxy moiety of compounds of Formula 7a maybe activated to halide to afford a compound of Formula 10a

[0064] wherein X is I, Br, or Cl and

[0065] the compound of Formula 10a may be coupled with3-tetrahydropyridinyl-indole in the presence of base to provide acompound of Formula Ia.

[0066] In accordance with other aspects of the invention is provided amethod of preparing compounds of Formula 5:

[0067] wherein A, D, E, G, X and R″ are as defined for Formula I and R″is benzyl or substituted benzyl, comprising alkylating the compound ofFormula 4

[0068] with R″ protected glycidyl ethers

[0069] wherein R″ is benzyl or substituted benzyl. In some embodimentsof the invention A is nitrogen, D is carbon substituted with methyl, andE and G are unsubstituted carbon.

[0070] Further in accordance with the present invention is provided amethod of preparing compound of Formula 6

[0071] where A, D, E and G are as defined for Formula I, and R″ isbenzyl or substituted benzyl, comprising the step of cyclizing acompound of Formula 5

[0072] with palladium or copper catalyst. In some embodiments of theinvention A is nitrogen, D is carbon substituted with methyl, and E andG are unsubstituted carbon.

[0073] Further in accordance with the invention is provided a method ofpreparing compound of Formula 8

[0074] wherein A, D, E and G are defined as for Formula I and R′″ is anaryl- or alkyl-sulfonate; comprising activating the hydroxy moiety ofthe compound of Formula 7

[0075] with a sulfonating reagent. In some embodiments of the inventionA is nitrogen, D is carbon substituted with methyl, and E and G areunsubstituted carbon.

[0076] Further in accordance with the invention is provided a method ofpreparing compound of Formula 10

[0077] wherein A, D, E and G are as defined for Formula I, and X is I,Cl or Br, comprising activating compound of Formula 7

[0078] to halide with halophosphorous such as phosphorous triiodide,phosphorous tribromide or phosphorous pentachloride, or with thionylhalide or any standard halogenating reagent.

[0079] Further in accordance with the present invention is provided amethod of preparing compound of Formula 7

[0080] wherein A, D, E and G are as defined Formula I, comprisingdebenzylating a compound of Formula 6

[0081] where R″ is benzyl or substituted benzyl.

[0082] In some embodiments of the invention A is nitrogen, D is carbonsubstituted with methyl and E and G are unsubstituted carbon.

[0083] In some embodiments of the invention compound of Formula 2

[0084] is halogenated with a halogenating agent such asN-halosuccinimide wherein halo means bromo-, chloro-, or iodo- in asuitable solvent such as acetonitrile.

[0085] In other embodiments of the invention compound of Formula 3

[0086] is demethylated with a Lewis acid in a solvent or a strong proticacid. Preferred Lewis acids include, but are not limited to, borontribromide, boron trichloride, aluminum trichloride, ferric chloride,trimethylsilyl iodine. The preferred solvent is methylene chloride.Strong protic acids include, but are not limited to, HBr and HCl.

[0087] Compound of Formula 4

[0088] may be alkylated with R” protected glycidyl ethers

[0089] wherein R″ is benzyl or substituted benzyl in a polar solvent.For instance R″ may be benzyl, 4-bromobenzyl, 4-chlorobenzyl,3,4-dimethoxybenzyl, 2- or 4-nitrobenzyl, or 4-methoxyphenyl.

[0090] Exemplary polar solvents useful in alkylation of compounds ofFormula 4 include dimethylsulfoxide (DMSO), dimethylforamide (DMF),dimethylacetamide (DMA).

[0091] Alkylation may be performed in the presence of a base such as,but not limited to, triethylamine, sodium carbonate, or potassiumcarbonate.

[0092] Compound of Formula 5 can be cyclized using palladium catalystssuch as, but not limited to, tris(dibenzylideneacetone)dipalladium,tetrakis(triphenyl-phosphine)palladium, or palladium acetate withphosphine ligands including but not limited to (±)2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl (BINAP) and separateenantiomers thereof; (±) 2,2′-bis(di-p-tolyl-phosphino)-1,1′-binaphthyl(Tol-BINAP) and separate enantiomers thereof;1-1′-bis(diphenylphosphino)ferrocene; 1,3-bis(diphenylphosphino)propane;and 1,2 bis(diphenylphosphino)ethane in the presence of bases such assodium hydride (NaH), lithium hydride (LiH), potassium hydride (KH),potassium carbonate, sodium carbonate, titanium carbonate, cesiumcarbonate, potassium t-butoxide or potassium phosphate tribasic insuitable solvent such as toluene.

[0093] Alternatively, compound of Formula 5 can be cyclized with coppercatalyst such as copper iodide in the presence of bases such as NaH,LiH, KH in a suitable solvent such as toluene.

[0094] Debenzylation of compound of Formula 6 can be carried out withLewis acids such as boron tribromide, boron trichloride, aluminumtrichloride, ferric chloride, trimethylsilyl iodine in a suitablesolvent such as methylene chloride.

[0095] Debenzylation of compound of Formula 6 may also be carried outwith strong protic acids such as HBr and HCl, or alternatively, underreductive cleavage conditions using Pd catalyst and hydrogen transferreagents such as hydrogen, cyclohexene, methyl cyclohexene, or ammoniumformate.

[0096] The hydroxy moiety of compound of Formula 7 is activated with asulfonating reagent such as aryl or alkyl sulfonyl chloride or alkyl oraryl sulfonic anhydride in the presence of a base such as triethylamineor pyridine in suitable solvents such as methylene chloride,tetrahydrofuran (THF), or toluene. Alkyl, as used herein preferablyrefers to alkyl of 1-6 carbon atom. Aryl, as used herein preferablyrefers to phenyl. Preferred sulfonating reagents include, but are notlimited to p-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3-or 4-nitrobenzenesulfonyl chloride, 2- or 4-bromo-benzenesulfonylchloride, or trifiluoromethylsulfonic anhydride.

[0097] Alternatively the hydroxy moiety of compound of Formula 7 isactivated as halogen, such as 1, Br or Cl with reagent such as I₃P, Br₃PCl₅P or SOCl₂ to provide compound of Formula 10.

[0098] Compound of Formula 8 or 10 are coupled with azaheterocycles ofFormula 9 including 3-tetrahydropyridinyl-indole in the presence ofbases such as sodium carbonate, potassium carbonate, or Hunig's base insuitable polar solvents such as THF, dioxane, DMSO, DMF, or DMA toafford compound of Formula I.

[0099] Still further in accordance with the present invention areprovided novel intermediates of the formula

[0100] wherein:

[0101] R₇ is hydroxy, alkoxy of 1-6 carbon atoms, or alkoxy of theformula

[0102] OH ;

[0103] wherein R₉ is hydroxy, benzyl ether, substituted benzyl etherssuch as 4-bromo-benzyl ether, 4-chlorobenzyl ether, 3,4-dimethoxybenzylether, 2- or 4-nitrobenzyl ether, or 4-methoxyphenyl; and

[0104] R₈ is halogen or hydrogen; and salts thereof.

[0105] A is nitrogen and D is carbon in preferred intermediates ofFormula II.

[0106] Also in accordance with the present invention are novelintermediates of the formula

[0107] wherein:

[0108] R₁₀ is hydroxy, halide or aryl or alkyl sulfonates; and saltsthereof.

[0109] A is nitrogen and D is carbon in preferred intermediates ofFormula III.

[0110] Certain compounds of the present invention contain one asymmetriccarbon atom, giving rise to enantiomeric forms of the compounds. It isto be understood that the invention encompasses the enantiomers thereofincluding racemic mixtures.

[0111] It is known that compounds possessing a basic nitrogen can becomplexed with many different acids (both protic and non-protic). Theinvention also includes acceptable salt forms formed from the additionreaction with either inorganic or organic acids. Inorganic acids such ashydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid (HI),sulfuric acid, phosphoric acid, nitric acid are useful as well asorganic acids such as acetic acid, propionic acid, citric acid, maleicacid, malic acid, tartaric acid, phthalic acid, succinic acid,methanesulfonic acid, toluenesulfonic acid, napthalenesulfonic acid,camphorsulfonic acid, benzenesulfonic acid are useful.

[0112] “Halo” as used herein, such as in the term “halosuccinimide”refers to halogen and preferably bromo-, chloro-, or iodo-.

DETAILED DESCRIPTION OF INVENTION

[0113] Thus, in accordance with the present invention is provided aprocess for preparing in high yield enantiomerically pure compounds ofFormula I as well as intermediate thereof.

[0114] The process of the present invention can be illustrated by thefollowing reaction scheme (Scheme I), wherein A, D, E, G, R′, R″, R′″,and X are as stated above. The reagents and the solvents for theindividual step are given for illustrative purposes only and may bereplaced by reagents and solvents known to those skilled in the art.

[0115] This process is characterized by high yields and purity of theproducts and technical convenience. The synthesis of compound Icomprises steps that begin with halogenation of 2 with halogenatingreagents such as N-halosuccinimide in acetonitrile to give 3.Deprotecting 3 with Lewis acids such as boron tribromide, borontrichloride, aluminum trichloride, ferric chloride, or trimethylsilyliodide in a suitable solvent such as methylene chloride, or with strongprotic acids such as HBr and HCl to give the salt of 4. Free base 4 isvery water soluble and neutralization is achieved from an Amberlyst A-21resin slurry in polar solvents such as ethanol or methanol.

[0116] Alkylation of 4, either as the free base or as the salt, withbenzyl or substituted benzyl protected glycidyl ethers in suitable polarsolvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), ordimethyl acetamide (DMA) in the presence of bases such as sodiumcarbonate, potassium carbonate, or triethylamine gives 5.

[0117] Compound 5 is cyclized using palladium catalysts such astris(dibenzylideneacetone)dipalladium,tetrakis(triphenylphosphine)palladium, or palladium acetate with ligandsfrom the group consisting of (±)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) and separateenantiomers thereof; (±) 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl(Tol-BINAP) and separate enantiomers thereof;1-1′-bis(diphenyl-phosphino)ferrocene;1,3-bis(diphenyl-phosphino)propane; and1,2-bis(diphenyl-phosphino)ethane in the presence of bases such as NaH,LiH, KH, potassium carbonate, sodium carbonate, titanium carbonate,cesium carbonate, potassium t-butoxide or potassium phosphate tribasicin suitable solvent such as toluene; or alternatively, with coppercatalyst such as copper iodide in the presence of bases such NaH, LiH,KH in a suitable solvent such as toluene to afford quinoline 6. Similardioxanes may also be prepared using the above reagents.

[0118] Deprotection of quinoline 6 with Lewis acids such as borontribromide, boron trichloride, aluminum trichloride, ferric chloride,trimethylsilyl iodide in a suitable solvent such as methylene chloride,or with strong protic acids such as HBr and HCl or under reductivecleavage conditions using Pd catalyst and hydrogen transfer reagentssuch as hydrogen, cyclohexene, methyl cyclohexene, or ammonium formateto gives 7. The hydroxyl moiety of 7 can be activated with a sulfonatingreagent such as an aryl or alkyl sulfonyl chloride or aryl or alkylsulfonic anhydride such as p-toluenesulfonyl chloride, methanesulfonylchloride, 2-, 3- or 4-nitro-benzenesulfonyl chloride, 2- or4-bromobenzenesulfonyl chloride, or trifluoromethylsulfonic anhydride inthe presence of bases such as triethylamine or pyridine in suitablesolvents such as methylene chloride, THF, or toluene to afford 8. Thefinal coupling of 8 with azaheterocycle 9, prepared by reaction ofindole with the hydrochloride salt of 4-piperidone, in the presence ofbases such as Hunig's base, potassium carbonate, or sodium carbonate inpolar solvents such as THF, dioxane, DMSO, DMF, or DMA affords finalcompound 1.

[0119] The following examples illustrate the process of the presentinvention but are not meant to be limiting thereof.

EXAMPLE 1 Preparation of 5-Bromo-6-Methoxy-2-Methylquinoline

[0120]

[0121] A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol) inacetonitrile (1.77 L) was cooled to 0-3° C. followed by portion-wiseaddition of N-bromosuccinimide (200 g, 1.12 mol) over a period of 30 minwhile maintaining the same temperature. The resulted brown slurry waswarmed to ambient temperature and stirred for an additional 6 h. Thereaction was then quenched by a 10% NaHSO₃ solution (211 mL). Thereaction mixture was concentrated to a volume of 600 mL then slowlypoured into 0.1 N NaOH (2.5 L). The slurry (pH=9) was stirred at roomtemperature for 1 h then filtered, washed with water (2×1 L) and driedin a vacuum oven to give 253 g (98.6%) of the title compound as a brownsolid.

[0122] R_(f)=0.39 (3:7) EtOAc:heptane;

[0123]¹H NMR (DMSO) δ 8.30 (d, J=6.5 Hz, 1H), 7.98 (d, J=6.9 Hz, 1H),7.70 (d, J=7.0 Hz, 1H), 7.47 (d, J=6.5 Hz, 1H), 4.02 (s, 3H), 2.66 (s,3H);

[0124]¹³C NMR (DMSO) δ 156.9, 153.1, 143.2, 133.6, 129.3, 126.0, 123.6,117.0, 106.1, 56.9, 24.3;

[0125] IR (KBr): υ_(max) 3435, 3197, 2943, 2843, 1699, 1613, 1599, 1495,1342, 1305, 1267, 1131, 1067, 968, 870, 811, 629 cm⁻¹;

[0126] Analysis for C₁₁H₁₀NOBr: Calculated: C, 52.40; H, 3.97; N, 5.56.Found: C, 52.13; H, 3.94; N, 5.61.

EXAMPLE 2 Preparation of the Hydrobromide Salt of5-Bromo-2-Methyl-6-Quinolinol

[0127]

[0128] A mixture of 5-bromo-2-methyl-6-methoxyquinoline (30 g, 0.12 mol)in 48% HBr (135 mL) was heated to reflux for 7 h then cooled to 5° C. in1 h to give a brown and thick slurry. The slurry was stirred at 0-5° C.for 1 h then filtered, washed with EtOAc (2×50 mL) and dried in a vacuumoven to give 34.9 g (92%) of the title compound as a brown solid.

[0129]¹H NMR (DMSO) δ 8.26 (d, J=8.7 Hz, 1H), 7.85 (d, J=9.1 Hz, 1H),7.56 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 2.64 (s, 3H);

[0130]¹³C NMR (DMSO) δ 155.7, 152.0, 142.8, 133.3, 128.9, 126.4, 123.3,121.2, 103.3, 24.1.

EXAMPLE 3 Preparation of 5-Bromo-2-Methyl-6-Quinolinol

[0131]

[0132] A slurry of the hydrobromide salt of5-bromo-2-methyl-6-quinolinol (3.4 g, 10.5 mmol) and Amberlyst A-21ion-exchange resin (1.7 g, pre-washed with MeOH then dried in oven) inMeOH (35 mL) was stirred at room temperature for 3 h. The mixture wasthen filtered and concentrated in vacuo to give 2.5 g (100%) of a yellowsolid.

[0133] R_(f)=0.36 (1:1) EtOAc:heptane;

[0134]¹H NMR (DMSO) δ 8.26 (d, J=8.4 Hz, 1H), 7.82 (d, J=9.3 Hz, 1H),7.47 (t, J=9.1 Hz, 2H), 2.66 (s, 3H);

EXAMPLE 4 Preparation of(2S)-1-(Benzyloxy)-3-[(5-Bromo-2-Methyl-6-Quinolinyl)Oxyl]-2-Propanol

[0135]

[0136] A solution of 5-bromo-2-methyl-6-quinolinol (30.1 g, 126 mmol),(R)-benzyl glycidyl ether (24.9 g, 152 mmol) and triethylamine (17.4 g,172 mmol) in DMA (200 mL) was heated in a 95-98° C. oil bath for 2 days.The solution was cooled and poured into water (300 mL) while stirring.The tan precipitate formed was filtered, washed with water (100 mL) anddried in a vacuum oven to give 37 g (73%) of the title compound as a tansolid.

[0137] R_(f)=0.35 (EtOAc);

[0138]¹H NMR (DMSO) δ 8.31 (d, J=8.8 Hz, 1H), 7.96 (d, J=9.2 Hz, 1H),7.72 (d, J=9.3 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.25-7.36 (m, 5H), 5.28(d, J=5.1 Hz, 1H), 4.56 (s, 2H), 4.22-4.29 (m, 2H), 4.08-4.15 (m, 1H),3.61-3.73 (m, 2H), 2.66 (s, 3H);

[0139]¹³C NMR (DMSO) δ 157.0, 152.7, 143.4, 138.4, 133.7, 129.2, 128.1,127.4, 127.3, 126.0, 123.6, 118.4, 106.8, 72.4, 71.3, 71.2, 68.1, 24.3;

[0140] IR (KBr): υ_(max) 3391, 3188, 2938, 2875, 1597, 1497, 1268, 1061,817, 697 cm⁻¹;

[0141] Specific rotation=+6.2° (c=1, CH₃OH);

[0142] Analysis for C₂₀H₂₀BrNO₃: Calculated: C, 59.66; H, 4.97; N, 3.48.Found: C, 59.43; H, 4.97; N, 3.55.

EXAMPLE 5 Preparation of(2S)-1-(Benzyloxy)-3-[5-Bromo-2-Methyl-6-Quinolinyl)Oxyl]-2-Propanolfrom 5-Bromo-2-Methyl-6-Quinolinol Salt

[0143]

[0144] In a rapidly stirred mixture of K₂CO₃ (597 g, 4.32 mol)) in DMF(3 L), HBr salt of 5-bromo-2-methyl-6-quinolinol (551 g, 1.73 mol) wasadded over 30-60 min at rt. After cooling the mixture to roomtemperature, (R)-benzyl glycidyl ether (353 g, 2.07 mol) was addedrapidly. The reaction mixture was then heated to 70° C. for from 50-70 hbefore cooling to 20-23° C. Water (6.05 L) was added over a period of30-120 min. The reaction mixture was filtered and the filtered cake waswashed with additional water (1 L). The solid was then stirred in water(3 L) for 30-40 min and filtered. The filtered cake was washed withwater (1 L). The solid obtained was then dried in a vacuum oven (5-0.5mm Hg) at 65° C. over 8-16 h to give 662 g of the title compound. Thecrude product was then recrystallized in EtOH (2.5 L) to give 487 g(70%) of the title compound as an off-white solid.

EXAMPLE 6 Palladium Catalyzed Preparation of(2S)-2[(Benzyloxy)methyl]-8-methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinoline

[0145]

[0146] A solution of(2S)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol (10g, 24.9 mmol), potassium phosphate tribasic (11.4 g, 50 mmol), Pd(OAc)₂(280 mg, 1.25 mmol) and racemic BINAP (1.55 g, 2.49 mmol) in toluene (50mL) was heated in a 100-102° C. oil bath for 3 d. The solution wascooled to room temperature then EtOAc (50 mL) and water (50 mL) wereadded. The reaction mixture was filtered through a bed of celite. Thetwo layers were separated. The aqueous layer was extracted with EtOAc(30 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo to give 8 g (100%) of the crude product as abrown syrup. The crude product can be carried through the debenzylationstep before purification. A sample of the crude mixture was purified onSiO₂, eluted with (3:1) hexane:EtOAc gave the title compound as a yellowoil which solidified upon standing.

[0147] R_(f)=0.5 (EtOAc);

[0148]¹H NMR (DMSO) δ 8.24 (d, J=8.6 Hz, 1H), 7.46 (d, J=9.2 Hz, 1H),7.27-7.38 (m, 7H);

[0149]¹³C NMR (DMSO) δ 156.4, 143.3, 138.1, 137.9, 135.2, 128.4, 128.2,127.2, 127.4, 121.4, 121.0, 120.9, 118.1, 72.5, 72.4, 68.2, 65.1, 24.5;

[0150] IR (KBr): υ_(max) 3413, 3280, 3028, 2917, 2886, 3798, 1628, 1601,1572, 1485, 1453, 1374, 1257, 1100, 1056, 982 cm⁻¹;

[0151] Specific Rotation=+7.9° (c=1.2, CHCl₃);

[0152] Analysis for C₂₀H₁₉NO₃: Calculated: C, 74.68; H, 5.91; N, 4.36.Found: C, 74.48; H, 6.03; N, 4.14.

EXAMPLE 7 Copper Catalyzed Preparation of(2S)-2[(Benzyloxy)methyl-8-methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinoline

[0153]

[0154] To a mixture of(2S)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol(100 g, 0.249 mol) and copper (I) iodide (47.4 g, 0.249 mol) in toluene(2 L), NaH (10.9 g, 0.45 mol) was added in portions at 30-35° C. over 20min. The reaction mixture was kept at 35° C. for 30 min then heated to110° C. slowly. After 30 min, the reaction was cooled to 600C,additional NaH (10.9 g, 0.45 mol) was added. This was warmed to 110° C.for an additional 2 hours then cooled to rt before dropwise addition ofwater (200 mL). After stirring for −15 min, the mixture was filteredthrough a bed of celite then washed with toluene (3×50 mL) and water (50mL). The two layers were separated. The organic layer was extracted withwater (100 mL), NH₄OH (100 mL), 25% NaCl (100 mL) and concentrated invacuo to give 387.6 g of the crude product as a brown syrup. The crudeproduct was carried through to the debenzylation step beforepurification (see example 10).

EXAMPLE 8 Lewis Acid Catalyzed Preparation of[(2R)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methanol

[0155]

[0156] To a solution of(2R)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline (0.74 g, 2.3 mmol) in CH₂Cl₂ (16 mL) being cooled in anice-bath, FeCl₃ (1.9 g, 12 mmol) was added. After 1 h, the ice-bath wasremoved and the reaction mixture was stirred for another 17 h. CHCl₃ (30mL) and 1 N NaOH (50 mL) were added to result in a suspension which wasthen filtered. The filtered solid was washed with CH₃OH (50 mL). Thecombined organic layers were concentrated in vacuo. Purification onSiO₂, eluted with (10:1) CHCl₃:iPrOH gave 0.45 g (84%) of the titlecompound as an off-white solid.

[0157] R_(f)=0.34 (EtOAc);

[0158]¹H NMR (DMSO) δ 8.29 (d, J=6.6 Hz, 1H), 7.42 (d, J=6.6 Hz, 1H),7.30-7.37 (m, 2H), 5.13 (t, J=4.3 Hz, 1H), 4.43-4.46 (m, 1H), 4.31-4.33(m, 1H), 4.09-4.14 (m, 1H), 3.70-3.78 (m, 2H), 2.60 (s, 3H);

[0159]¹³C NMR (DMSO) δ 156.7, 143.6, 138.4, 135.9, 129.0, 121.7, 121.4,121.1, 118.5, 78.4, 74.4, 65.6, 60.3, 24.9;

[0160] IR (KBr): υ_(max) 3200, 2917, 2849, 1628, 1601, 1488, 1374, 1341,1265, 1107, 1079, 1050, 809 cm⁻¹;

[0161] GC/MS 231, 212, 200, 186, 175, 168, 156, 145, 129, 117, 110, 102,89, 76,64, 57, 50, 39, 31.

EXAMPLE 9 Palladium Catalyzed Preparation of[(2S)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methanol

[0162]

[0163] To a solution of(2S)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline (0.16 g, 0.5 mmol) in EtOH (1 mL) was added cyclohexene(0.5 mL) then 10% Pd/C (0.016 g, 10 mol %). The mixture was heated toreflux under N₂ for 18 h then cooled and filtered. The catalyst wasrinsed with methanol and the filtrate was concentrated in vacuo toafford 0.113 g (98%) of the title alcohol as an off-white solid.

[0164]¹H NMR (CD₃OD) δ 8.46 (m, 1H), 7.47 (m, 1H), 7.38-7.31 (m, 2H),4.40 (m, 1H), 4.36 (m, 1H), 4.18 (m, 1H), 3.91 (m, 2H), 2.68 (s, 3H).

EXAMPLE 10 Protic Acid Catalyzed Preparation of[(2S)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methanol

[0165]

[0166] A mixture of crude(2S)-2[(benzyloxy)methyl-2,3-dihydro[1,4]dioxino [2,3-f]-quinolineproduct mixture (57.6 g, 0.179 mol) from example 7 in toluene (300 mL)was mixed with 20% HCl (436 g, 3.59 mol) and heated at 80° C. After 30min, the reaction mixture was cooled to room temperature. The two layerswere separated. A 30% NH₄OH solution (400 mL) was added to the aqueouslayer at 10-20° C. to pH 10. This was stirred for 30 min, the solid wasfiltered, washed with water and recrystallized from CH₃OH (200 mL) togive 25.7 g (61.9%) of the title alcohol as an off-white solid.

EXAMPLE 11 Preparation of[(2R)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methyl4-Bromobenzenesulfonate

[0167]

[0168] A solution of[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-methanol(4.0 g, 17.3 mmol), brosyl chloride (4.86 g, 19.0 mmol), dimethylaminopyridine (20 mg, 0.16 mmol) and triethylamine (3.62 mL, 25.8 mmol) intoluene (40 mL) was stirred at 60° C. for 6 h. The reaction mixture wascooled to room temperature then water (20 mL) was added. After 30 min,the two layers were separated. The organic layer was extracted with 8%NaHCO₃ (20 mL) and H₂O (20 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The solid obtained was dissolved in isopropylalcohol (50 mL) and toluene (10 mL) at 80° C., cooled to roomtemperature over 1 h then filtered, washed with (5:1) IPA: toluene (2×5mL) and dried in a vacuum oven to give 5.99 g (76.9%) of the titlecompound as an off-white solid.

[0169]¹³C NMR (CDCl₃) δ 157.9, 144.3, 138.1, 134.7, 132.9, 129.7, 129.6,129.0, 122.4, 121.7, 121.3, 118.8, 70.7, 67.6, 64.5, 25.4

EXAMPLE 12 Preparation of[(2R)-8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methyl4-Methylbenzenesulfonate

[0170]

[0171] A solution of[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-methanol(0.13 g, 0.57 mmol), tosyl chloride (0.16 g, 0.82 mmol) andtriethylamine (0.65 mL, 4.7 mmol) in CH₂Cl₂ (8 mL) was stirred at roomtemperature for 18 h. CHCl₃ (30 mL) and H₂O (30 mL) were added. The twolayers were separated. The aqueous layer was extracted with CHCl₃ (20mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. Purification on SiO₂, eluting with (1:1)hexane:EtOAc gave 0.19 g (88%) of the title compound as a brown syrup.

[0172] R_(f)=0.43 (CHCl₃:iPrOH);

[0173] mp: 115-117° C.;

[0174]¹H NMR (CDCl₃) δ 8.12 (d, J=8.6 Hz, 1H), 7.76 (m, 2H), 7.51 (d,J=9 Hz, 1H), 7.20-7.60 (m, 4H), 4.5-4.6 (m, 1H), 4.2-4.4 (m, 3H),4.1-4.2 (m, 1H), 2.70 (s, 3H), 2.39 (s, 3H);

[0175]¹³C NMR (DMSO) δ 156.9, 145.4, 143.6, 137.9, 134.7, 132.2, 130.4,128.7, 128.0, 121.8, 121.6, 121.3, 121.3, 118.3, 70.9, 68.6, 64.1, 60.1,24.9, 21.4, 21.1, 14.4;

[0176] GC/MS 385, 213, 186, 174, 145, 130, 117, 102, 91, 77, 65, 52, 41,30;

[0177] IR (KBr): υ_(max) 3625, 3374, 2924, 1732, 1628, 1601, 1573, 1485,1359, 1251, 1177, 1096, 1049, 941, 818, 664, 554 cm⁻¹.

EXAMPLE 13 Formation of 3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-Indole

[0178]

[0179] A mixture of indole (1.01 g, 8.59 mmol), 4-piperidone monohydratehydrochloride (1.99 g, 12.9 mmol) and KOH (1.74 g, 31 mmol) in CH₃OH (9mL) was heated to reflux for 21 h. After cooling the reaction mixture toroom temperature, H₂O (14 mL) was added. The suspension was filtered,the solid was washed with (1:1) MeOH:H₂O (20 mL) and air-dried to give1.49 g (87%) of the title compound as an off-white solid.

[0180]¹H NMR (DMSO) δ 11.1 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.3-7.5 (m,2H), 7.0-7.2 (m, 2H), 6.16 (m, 2H), 3.3-3.5 (m, 2H), 2.9 (t, J=5.7 Hz,2H), 2.38 (m, 2H);

[0181]¹³C NMR(DMSO) δ 137.0, 130.1, 124.7, 122.3, 121.1, 120.1, 119.9,119.1, 116.7, 111.7, 45.0, 43.0, 40.1, 39.9, 39.7, 39.5, 39.3, 39.3,39.1, 38.9, 28.3.

EXAMPLE 14 Preparation of(2S)-2-[4-(1H-Indol-3-yl)-3,6-Dihydro-2H-Pyridin-1-ylmethyl]-8-Methyl-2,3-Dihydro-1,4-Dioxino[2,3-f]Quinoline

[0182]

[0183] A solution of[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl4-methylbenzenesulfonate (0.192 g, 0.499 mmol),3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.119 g, 0.601 mmol) andK₂CO₃ (0.104 g, 0.753 mmol) in (1:1) THF:DMF (1.4 mL) was heated to80-83° C. for 10 h. After this time, H₂O (3 mL) was added and thesuspension was filtered. The filtered solid was washed with CH₃OH (2×3mL), Et₂O (2×5 mL) and air-dried to give 0.148 g (72%) of the titlecompound as a tan solid.

[0184] R_(f)=0.18 (EtOAc);

[0185]¹H NMR (DMSO) δ 11.1 (s, 1H), 8.26 (d, J=8.6 Hz, 1H), 7.82 (d,J-7.8 Hz, 1H), 7.25-7.50 (m, 4H), 6.9-7.2 (m, 2H), 6.14 (s, 1H), 4.4-4.7(m, 2H), 4.0-4.2 (m, 1H), 2.7-3.0 (m, 4H), 2.4-2.7 (m, 8H);

[0186]¹³C NMR (DMSO) δ 156.8, 146.8, 143.6, 138.4, 137.3, 135.6, 130.0,128.9, 125.0, 123.1, 121.8, 121.6, 121.5, 121.2, 120.4, 119.6, 118.5,117.9, 116.2, 112.1, 72.1, 66.8, 58.0, 53.8, 51.1, 28.9, 24.9;

[0187] IR (KBr): υ_(max) 3410, 3240, 3059, 2848, 1601, 1484, 1403, 1352,1255,1096, 982, 818, 745 cm⁻¹.

EXAMPLE 15 Preparation of(2S)-2-[4-(1H-Indol-3-yl)-3,6-Dihydro-2H-Pyridin-1-ylmethyl]-8-Methyl-2,3-Dihydro-1,4-Dioxino [2,3-f]Quinoline

[0188]

[0189] A solution of[(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl4-bromobenzenesulfonate (2.0 g, 4.44 mmol),3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.01 g, 5.09 mmol) anddiisopropylethyl amine (0.86 g, 6.65 mmol) in DMSO (10 mL) was heated to80-83° C. After 10 h, the reaction mixture was cooled to 65-70° C.before CH₃OH (3 mL) was added. The resulted suspension was cooled toroom temperature, filtered, washed with CH₃OH and dried in a vacuum ovento give 1.3 g (71%) of the title compound as a yellow solid.

EXAMPLE 16 Preparation of(2R)-1-(Benzyloxy)-3-[5-Bromo-2-Methyl-6-Quinolinyl)Oxyl]-2-Propanolfrom 5-Bromo-2-Methyl-6-Quinolinol

[0190]

[0191] A solution of 5-bromo-2-methyl-6-quinolinol (2.50 g, 10.5 mmol),(S)-benzyl glycidyl ether (2.1 g, 12.8 mmol) and triethylamine (0.54 g,5.3 mmol) in DMA (25 mL) was heated in a 80-83° C. oil bath for 2 d. Thesolution was cooled and poured into water (20 mL) while stirring. Thetan precipitate formed was filtered, washed with water (10 mL) and driedin a vacuum oven to give 3.0 g (71%) of the title compound as a tansolid.

EXAMPLE 17 Preparation of1-(Benzyloxy)-3-[5-Bromo-2-Methyl-6-Quinolinyl)Oxyl]-2-Propanol from5-Bromo-2-Methyl-6-Quinolinol Salt

[0192]

[0193] A solution of 5-bromo-2-methyl-6-quinolinol (1.0 g, 4.2 mmol),benzyl glycidyl ether (0.83 g, 5.1 mmol) and triethylamine (0.21 g, 2.1mmol) in DMA (15 mL) was heated in a 90-95° C. oil bath for 18 h. Thesolution was cooled and poured into water (30 mL) and Et₂O (100 mL). Thetwo layers were separated. The aqueous layer was extracted with Et₂O(2×50 mL). The organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give 1.3 g (74%) of the titled compound as atan solid.

EXAMPLE 18 Palladium Catalyzed Preparation of(2R)-2[(Benzyloxy)methyl]-8-methyl-2,3-Dihydro[1,41Dioxino[2,3-f]Quinoline

[0194]

[0195] A mixture of(2R)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol(2.9 g, 7.2 mmol) and NaH (0.48 g, 12 mmol) in toluene (15 mL) wasstirred in a 50-52° C. oil bath for 40 min. This was then canulated intoa mixture of Pd(OAc)₂ (82 mg, 0.36 mmol) and racemic BINAP (451 mg,0.724 mmol) in toluene (10 mL) in a 50-52° C. oil bath. The resultedreaction mixture was degassed 3 times with Ar before heated to 100-102°C. in an oil bath. After 20 h, the reaction mixture was cooled to roomtemperature then sat'd NH₄Cl (60 mL) and EtOAc (60 mL) were added. Thiswas stirred for 20 min before filtering through a bed of celite. The twolayers were separated. The organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo. Purification on SiO₂, eluting with (3:1)hexane:EtOAc gave 1.4 g (56%) of the title compound as a brown oil.

EXAMPLE 19 Palladium Catalyzed Preparation of2[(Benzyloxy)methyl]-8-methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinoline

[0196]

[0197] A mixture of1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol (1.1 g,2.7 mmol) and NaH (175 mg, 4.4 mmol) in toluene (10 mL) was stirred in a50-52° C. oil bath for 30 min. This was then canulated into a mixture ofPd(OAc)₂ (31 mg, 0.14 mmol) and (R)-Tol-BINAP (186 mg, 0.274 mmol) intoluene (10 mL) in a 50-52° C. oil bath. The resulted reaction mixturewas degassed 3 times with Ar before heated to 100-102° C. in an oilbath. After 18 h, the reaction mixture was cooled to room temperaturethen sat'd NH₄Cl (30 mL) and EtOAc (30 mL) were added. This was filteredthrough a bed of celite. The two layers were separated. The aqueouslayer was extracted with EtOAc (2×20 mL). The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated in vacuo.Purification on SiO₂, eluting with (3:1) hexane:EtOAc gave 0.52 g (58%)of the title compound as a yellow oil.

EXAMPLE 20 Preparation of[8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin-2-yl]Methyl4-Methylbenzenesulfonate

[0198]

[0199] A solution of[8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-methanol (0.13 g,0.57 mmol), tosyl chloride (0.16 g, 0.82 mmol) and triethylamine (0.65mL, 4.7 mmol) in CH₂Cl₂ (8 mL) was stirred at room temperature for 18 h.CHCl₃ (30 mL) and H₂O (30 mL) were added. The two layers were separated.The aqueous layer was extracted with CHCl₃ (20 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo.Purification on SiO₂, eluting with (1:1) hexane:EtOAc gave 0.19 g (88%)of the title compound as a brown syrup.

[0200] R_(f)=0.44 (EtOAc);

[0201]¹H NMR (CDCl₃) δ 8.12 (d, J=8.6 Hz, 1H), 7.76 (m, 2H), 7.51 (d,J=9 Hz, 1H), 7.20-7.60 (m, 4H), 4.5-4.6 (m, 1H), 4.2-4.4 (m, 3H),4.1-4.2 (m, 1H), 2.70 (s, 3H), 2.39 (s, 3H).

EXAMPLE 21 Lewis Acid Catalyzed Preparation of[8-Methyl-2,3-Dihydro[1,4]Dioxino[2,3-f]Quinolin -2-yl]Methanol

[0202]

[0203] To a solution of2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino [2,3-f]quinoline(0.30 g, 0.94 mmol) in CH₂Cl₂ (8 mL) being cooled in an ice-bath, FeCl₃(0.77 g, 4.7 mmol) was added. After 1 h, the ice-bath was removed andthe reaction mixture was stirred for another 4 h. CH₂Cl₂ (30 mL) and 1NNaOH (25 mL) were added to result in a suspension which was thenfiltered. The filtered solid was washed with CH₃OH (50 mL). The combinedorganic layers were concentrated in vacuo. Purification on SiO₂, elutedwith (10:1) CHCl₃:iPrOH gave 0.15 g (68%) of the title compound as anoff-white solid.

What is claimed is: 1 A method of making compounds of Formula I:

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; R², R³, R⁴, and R⁶ are,independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbonatoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamidoof 1 to 6 carbon atoms R⁵ is hydrogen or alkyl of 1 to 6 carbon atoms; Adotted line represents an optional double bond; A and D are selectedfrom carbon, substituted by R¹, and nitrogen, provided that at least oneof A and D is nitrogen; E and G are carbon, substituted by R¹; and Z isN or CR⁶; or pharmaceutically acceptable salts thereof, comprising thesteps of: a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms; with a halogenating reagent toafford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3 inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4 with R” protected glycidylethers

 wherein R″ is benzyl or substituted benzyl to afford compound of theformula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 with witha sulfonating reagent to afford a compound of the formula:

 wherein R′″ is an aryl- or alkyl- sulfonate; and g) coupling thecompound of Formula 8 with the appropriate azaheterocycle of Formula 9

 in the presence of base to provide a compound of Formula I


2. A method of making compound of formula I:

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; R², R³, R⁴, and R⁶ are,independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbonatoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamidoof 1 to 6 carbon atoms R⁵ is hydrogen or alkyl of 1 to 6 carbon atoms; Adotted line represents an optional double bond; A and D are selectedfrom carbon substituted by R¹ and nitrogen, provided that at least oneof A and D is nitrogen; E and G are carbon, substituted by R¹; and Z isN or CR⁶; or pharmaceutically acceptable salts thereof, comprising thesteps of a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms; with N-halosuccinimide in asolvent to afford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3 inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4 with R″ protected glycidylethers

 wherein R″ is benzyl or substituted benzyl, or alkyl alcohol of 1 to 6carbon atoms to afford compound of the formula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 withalkyl- or aryl-sulfonyl chloride or with alkyl or aryl sulfonicanhydride in the presence of a base to afford a compound of the formula:

 wherein R′″is an alkyl- or aryl-sulfonate; and g) coupling the compoundof Formula 8 with the appropriate azaheterocycle of Formula 9

 in the presence of base to provide a compound of Formula I.
 3. A methodof making compound of Formula Ia:

comprising the steps: a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms;  with N-halosuccinimide in asolvent to afford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3 inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4 with R″ protected glycidylethers

 wherein R″ is benzyl or substituted benzyl;  to afford compound of theformula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 with alkylor aryl sulfonyl chloride with alkyl or aryl sulfonic anhydride in thepresence of a base to afford a compound of the formula:

 wherein R′″ is a alkyl- or aryl-sulfonate; and g) coupling the compoundof Formula 8 with 3-tetrahydropyridinyl-indole in the presence of baseto provide a compound of Formula Ia.
 4. The method of claim 1 whereinthe compound of Formula 2 is treated with N-halosuccinimide inacetonitrile.
 5. The method of claim 1 wherein the halogenation reactionis quenched with a 10% NaHSO₃ solution and the product precipitated withNaOH.
 6. The method of claim 1 wherein the compound of Formula 3 isdealkylated with a Lewis acid.
 7. The method of claim 1 wherein thecompound of Formula 3 is dealkylated with a protic acid.
 8. The methodof claim 7 wherein the protic acid is HBr.
 9. The method of claim 8wherein the compound of Formula 2 is heated to reflux in HBr for fromabout 6 to about 7 hours.
 10. The method of claim 1 wherein the compoundof Formula 4 is alkylated with benzyl- or substituted benzyl-glycidylether in a polar solvent.
 11. The method of claim 1 wherein the compoundof Formula 4 is alkylated with benzyl glycidyl ether, 4-bromobenzylglycidyl ether, 4-chlorobenzyl glycidyl ether, 3,4-dimethoxybenzylglycidyl ether, 2- or 4-nitrobenzyl glycidyl ether, or 4-methoxy-phenylglycidyl ether.
 12. The method of claim 10 wherein the polar solvent isdimethylsulfoxide, dimethyl-formamide, or dimethylacetamide.
 13. Themethod of claim 10 wherein the base is triethylamine, sodium carbonate,or potassium carbonate.
 14. The method of claim 1 wherein the compoundof Formula 5 is cyclized using palladium catalyst in the presence ofphosphine ligand and base.
 15. The method of claim 14 wherein thepalladium catalyst is tris(dibenzylideneacetone)dipalladium,tetrakis(triphenylphosphine)palladium, or palladium acetate withphosphine ligands selected from the group consisting of (+)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and separate enantiomersthereof; (+) 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl and separateenantiomers thereof; 1-1′-bis(diphenylphosphino)ferrocene;1,3-bis(diphenyl-phosphino)propane; and1,2-bis(diphenylphosphino)ethane.
 16. The method of claim 14 wherein thebase is sodium hydride, lithium hydride, potassium hydride, potassiumcarbonate, sodium carbonate, titanium carbonate, cesium carbonate,potassium t-butoxide or potassium phosphate tribasic.
 17. The method ofclaim 1 wherein the compound of Formula 5 is cyclized using coppercatalyst in the presence of base.
 18. The method of claim 17 wherein thecopper catalyst is copper iodide.
 19. The method of claim 17 wherein thebase is sodium hydride, lithium hydride or potassium hydride.
 20. Themethod of claim 1 wherein the compound of Formula 6 is debenzylated withLewis acid, strong protic acid or under reductive cleavage conditions.21. The method of claim 20 wherein the Lewis acid is boron tribromide,boron trichloride, aluminum trichloride, ferric chloride ortrimethylsilyl iodine.
 22. The method of claim 20 wherein the proticacid is hydrobromic acid or hydrochloric acid.
 23. The method of claim 1wherein a) the compound of Formula 5 is cyclized using copper catalystin the presence of NaH to provide compound of Formula 6, and b) compoundof Formula 6 is debenzylated with HCl to provide compound of Formula 7.24. The method of claim 20 wherein reductive cleavage is performed usingpalladium catalyst and hydrogen transfer reagents.
 25. The method ofclaim 24 wherein the palladium catalyst is Pd/C.
 26. The method of claim24 wherein the transfer reagent is cyclohexene, methylcyclohexene,ammonium formate or hydrogen.
 27. The method of claim 24 wherein thepalladium catalyst is Pd/C and the transfer reagent is cyclohexene. 28.The method of claim 1 wherein the compound of Formula 7 is activatedwith a sulfonating reagent or with an aryl or alkyl sulfonic anhydridein the presence of a base.
 29. The method of claim 28 wherein thecompound of Formula 7 is activated with p-toluenesulfonyl chloride,methanesulfonyl chloride, 2-, 3- or 4-nitrobenzenesulfonyl chloride, 2-or 4-bromobenzenesulfonyl chloride or trifluoromethylsulfonic anhydride.30. The method of claim 28 wherein the compound of Formula 7 isactivated with 4-bromobenzenesulfonylchloride.
 31. The method of claim28 wherein the base is triethylamine or pyridine in methylene chloride,tetrahydrofuran, or toluene.
 32. The method of claim 1 wherein thecompound of Formula 8 is coupled with an azaheterocycle of Formula 9 inthe presence of a base.
 33. The method of claim 32 wherein the base issodium carbonate, potassium carbonate, or Hunig's base.
 34. A method ofmaking compounds of Formula I:

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; R², R³, R⁴, and R⁶ are,independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbonatoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamidoof 1 to 6 carbon atoms R⁵ is hydrogen or alkyl of 1 to 6 carbon atoms; Adotted line represents an optional double bond; A and D are selectedfrom carbon, substituted by R¹, and nitrogen, provided that at least oneof A and D is nitrogen; E and G are carbon, substituted by R¹; and Z isN or CR⁶; or pharmaceutically acceptable salts thereof, comprising thesteps of: a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms;  with N-halosuccinimide in asolvent to afford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3 inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4 with R″ protected glycidylethers

 wherein R″ is benzyl or substituted benzyl to afford compound of theformula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 to ahalide to afford a compound of the formula:

 wherein X is I, Br or Cl and g) coupling the compound of Formula 10with the appropriate azaheterocycle of Formula 9

 in the presence of base to provide a compound of Formula I.
 35. Themethod of claim 34 wherein the compound of Formula 7 is activated with ahalogenating reagent.
 36. The method of claim 34 wherein the compound ofFormula 7 is activated as a halide with phosphorous triiodide,phosphorous tribromide, phosphorous pentachloride or thionyl chloride.37. A method of making compounds of Formula I:

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; R², R³, R⁴, and R⁶ are,independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbonatoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamidoof 1 to 6 carbon atoms R⁵ is hydrogen or alkyl of 1 to 6 carbon atoms; Adotted line represents an optional double bond; A and D are selectedfrom carbon, substituted by R¹, and nitrogen, provided that at least oneof A and D is nitrogen; E and G are carbon, substituted by R¹; and Z isN or CR⁶; or pharmaceutically acceptable salts thereof comprising thesteps of: a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms;  with N-halosuccinimide in asolvent to afford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3 inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4 with R″ protected glycidylethers

 wherein R″ is benzyl or substituted benzyl to afford compound of theformula:

d) cyclizing the compound of Formula 5 with palladium or copper catalystto afford a compound of the formula:

e) debenzylating the compound of Formula 6 to afford the compound of theformula:

f) activating the hydroxy moiety of the compound of Formula 7 to ahalide to afford a compound of the formula:

 wherein X is I, Br or Cl; and g) coupling the compound of Formula 10with the appropriate azaheterocycle of Formula 9

 in the presence of base to provide a compound of Formula I.
 38. Amethod of making a compound of Formula Ia:

comprising the steps: a) halogenating a compound of the formula:

wherein R′ is alkyl of 1-6 carbon atoms;  with N-halosuccinimide in asolvent to afford a compound of the formula:

wherein X is Br, Cl, or I; b) dealkylating the compound of Formula 3a inan acid to afford a compound of the formula:

c) alkylating the compound of Formula 4a with R″ protected glycidylethers

 wherein R″ is benzyl or substituted benzyl; to afford compound of theformula:

d) cyclizing the compound of Formula 5a with palladium or coppercatalyst to afford a compound of the formula:

e) debenzylating the compound of Formula 6a to afford the compound ofthe formula:

f) activating the hydroxy moiety of the compound of Formula 7a to ahalide to afford a compound of the formula:

 wherein X is I, Br or Cl; and g) coupling the compound of Formula 10awith 3-tetrahydropyridinyl-indole in the presence of base to provide acompound of Formula Ia.
 39. A method of preparing compounds of theformula 5:

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; A and D are selected fromcarbon substituted by R¹ and nitrogen, provided that at least one of Aand D is nitrogen; E and G are carbon, substituted by R¹; R″ is benzylor substituted benzyl; and X is halogen; comprising alkylating thecompound of formula 4

with R″ protected glycidyl ethers


40. The method of claim 39 wherein A is nitrogen, and D is carbon.
 41. Amethod of preparing a compound of Formula 6

R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two tosix carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6carbon atoms, amino, mono- or di-alkylamino in which each alkyl grouphas 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; A and D are selected fromcarbon substituted by R¹ and nitrogen, provided that at least one of Aand D is nitrogen; E and G are carbon, substituted by R¹; and R″ isbenzyl or substituted benzyl, comprising the step of cyclizing acompound of Formula 5

with palladium or copper catalyst.
 42. The method of claim 41 whereinthe catalyst is a palladium catalyst.
 43. The method of claim 41 whereinA is nitrogen and D is carbon.
 44. A method of preparing a compound ofFormula 10×

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; A and D are selected fromcarbon substituted by R¹ and nitrogen, provided that at least one of Aand D is nitrogen; E and G are carbon, substituted by R¹; and X is I, Clor Br: comprising activating compound of Formula 7

to halide with a standard halogenating reagent.
 45. The method of claim44 wherein the halogenating agent is halophosphorous.
 46. The method ofclaim 44 wherein the halophosphorous is phosphorous triiodide,phosphorous tribromide or phosphorous pentachloride.
 47. The method ofclaim 44 wherein A is nitrogen, and D is carbon.
 48. A method ofpreparing a compound of Formula 8

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; A and D are selected fromcarbon substituted by R¹ and nitrogen, provided that at least one of Aand D is nitrogen; E and G are carbon, substituted by R¹; and R′″ is anaryl- or alkyl- sulfonate; comprising activating the hydroxy moiety ofthe compound of formula 7

with aryl or alkyl sulfonyl chloride or with aryl or alkyl sulfonicanhydride in the presence of a base.
 49. The method of claim 48 whereinA is nitrogen and D is carbon.
 50. A method of preparing a compound ofFormula 7

wherein R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; A and D are selected fromcarbon substituted by R¹ and nitrogen, provided that at least one of Aand D is nitrogen; and E and G are carbon, substituted by R¹; comprisingdebenzylating a compound of Formula 6

where R″ is benzyl or substituted benzyl.
 51. The method of claim 50wherein A is nitrogen, and D is carbon.
 52. A compound of the formula

wherein: R¹ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; A and D are selected fromcarbon substituted by R¹ and nitrogen, provided that at least one of Aand D is nitrogen; E and G are carbon, substituted by R¹; R₇ is hydroxy,alkoxy of 1-6 carbon atoms, or alkoxy of the formula

 wherein R₉ is hydroxy, benzyl ether, substituted benzyl ethers such as4-bromobenzyl ether, 4-chlorobenzyl ether, 3,4-dimethoxybenzyl ether, 2-or 4-nitrobenzyl ether, or 4-methoxyphenyl; and R₈ is halogen orhydrogen; and salts thereof.
 53. A compound of claim 52 wherein A isnitrogen and D is carbon.
 54. A compound of the formula

wherein: R₁ is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxyof two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkylgroup has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, oralkanesulfonamido of 1 to 6 carbon atoms; A and D are selected fromcarbon substituted by R¹ and nitrogen, provided that at least one of Aand D is nitrogen; E and G are carbon, substituted by R¹; and R¹⁰ ishydroxy, halide or alkyl- or aryl- sulfonates; and salts thereof.
 55. Acompound of claim 54 wherein A is nitrogen and D is carbon.